Agonist Epitopes for Renal Cell Carcinoma


Approximately 30,000 patients are diagnosed with renal cell carcinoma (RCC) each year in the United States, and an estimated 12,000 patients die of this disease. Most patients are diagnosed with advanced local disease or metastatic disease. Metastatic RCC carries a poor prognosis with median survivals in the range of 10-12 months. Drugs that inhibit VEGF receptor tyrosine kinases such as Sorafenib and Sunitinib have recently been approved by the FDA to treat metastatic RCC. Although a significant percentage of patients will achieve a partial response or disease stabilization with these agents, complete responses are rare and disease progression eventually ensues. RCC is unusual among solid tumors as it appears to be susceptible to immunotherapy. Cytokines such as IL-2 and IFN-alpha nonspecifically stimulate the immune system resulting in disease regression. Unfortunately, these drugs achieve success in only a minority (15-20%) of the metastatic RCC patient population. Therefore, new methods are needed to improve on immune-based therapies and expand the curative potential of therapies for patients with RCC.

The present invention discloses peptides and antigen epitopes specific for RCC for use in the diagnosis, vaccination, or adoptive infusion of antigen specific T cells to treat patients with metastatic RCC. The immunogenic peptide, which binds to the HLA-A11 epitope, was identified in a patient with metastatic RCC that under went an investigational allogeneic hematopoietic stem cell transplant. Cancer regression occurred post-transplant consistent with a graft-vs-tumor effect. A T-cell line, expanded from the patient’s blood cells at the time of tumor regression, was isolated and subsequently shown to kill the patients RCC cells in vitro. Expression and sequencing studies revealed that the patient’s T-cells recognize an antigen epitope derived from a human endogenous retrovirus (HERV). Further, pre-clinical studies using quantitative real-time PCR found that this HERV was expressed in eight of 14 RCC tumor cell lines with no HERV expression in patient fibroblasts, hematopoietic cells or in c-DNAs analyzed from 48 different normal tissues. Plans are underway to investigate the immunogenic potential of this peptide to induce expansion of T-cells that are cytotoxic to RCC cells in vitro and in pre-clinical animal models.

Inventors:

Richard Childs (NHLBI)  ➽ more inventions...


Intellectual Property:
U.S. Pat: 9,856,453 issued 2018-01-02
U.S. Pat: 8,921,050 issued 2014-12-30
PCT Application No. PCT/US2007/64237
US Application No. 12/293,180
US Application No. 15/821,523
US Application No. 16/241,017

Publications:
I Espinoza-Delgado and RW Childs. Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy. Expert Rev Anticancer Ther. 2004 Oct;4(5):865-875. PubMed abs
Y Takahashi and RW Childs. Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma. Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6353S-6359S. PubMed abs
R Childs et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000 Sep 14;343(11):750-758. PubMed abs
Marco Bregni, Naoto T. Ueno, and Richard Childs. Meeting Report: The Second International Meeting on Allogeneic Transplantation in Solid Tumors (ATST). Bone Marrow Transplantation (Submitted 2006).

Collaboration Opportunity:

The Hematology Branch of the NHLBI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutic treatment approaches targeting this novel RCC antigen. Please contact Dr. Richard Childs at 301/594-8008 or childsr@nhlbi.nih.gov for more information.


Licensing Contact:
Michael Shmilovich, J.D.
Email: shmilovm@mail.nih.gov
Phone: 301-435-5019

OTT Reference No: E-122-2006-0
Updated: Jun 14, 2010